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Denosumab superior to bisphosphonate therapy for building BMD
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The human monoclonal antibody denosumab more effectively increases bone mass in patients with low bone mineral density or osteoporosis when compared against any bisphosphonate therapy, according to a meta-analysis of 10 randomized controlled trials.
“Our meta-analysis of head-to-head randomized controlled trials provides moderately strong evidence that denosumab is more effective at increasing BMD at all relevant anatomical sites vs. bisphosphonates,” Houchen Lyu, MD, PhD, a clinical research fellow in the division of rheumatology, immunology and allergy at Brigham and Women’s Hospital, told Endocrine Today. “Fracture risk reduction was similar, but few events limit the statistical power. Safety profiles between denosumab and bisphosphonates were similar.”
The researchers analyzed data from 10 randomized controlled trials with durations of at least 12 months conducted between 2006 and 2018, assessing adults with either osteoporosis or low BMD (n = 5,361). Mean age across trials ranged from 63 to 78 years, and 99% of participants were women. Participants received 60 mg subcutaneous denosumab (Prolia, Amgen) once every 6 months for at least 12 months (intervention group) or a bisphosphonate treatment (comparator group), including alendronate, ibandronate, risedronate or zoledronic acid. Primary outcomes were mean percentage change in BMD at the lumbar spine, total hip and femoral neck at 12 months. Secondary outcomes included mean percentage change in BMD at the lumbar spine, total hip and femoral neck at 24 months, overall incidence of vertebral fractures and overall incidence of nonvertebral fractures at 12 and 24 months, along with any adverse events.
Researchers used random-effects models to calculate pooled estimates for percentage changes in BMD.
Researchers found that, compared with all bisphosphonates, incremental 12-month increase in BMD with denosumab was greater by 1.42% (95% CI, 0.95-1.89) at the lumbar spine, 1.11% (95% CI, 0.91-1.3) at the total hip and 1% (95% CI, 0.78-1.22) at the femoral neck.
After removing five studies with participants with osteopenia, the mean BMD increase difference between treatments was 1.47% (95% CI, 0.97-1.96) at the lumbar spine, 1.04% (95% CI, 0.85-1.12) at the total hip and 0.97% (95% CI, 0.73-1.15) at the femoral neck. In subgroup analyses based on specific bisphosphonate treatments, researchers found that denosumab increased BMD more than each of the three oral bisphosphonates at all sites; however, denosumab only demonstrated superiority at the total hip and femoral neck sites when compared with zoledronic acid.
In two trials (n = 795) reporting changes in BMD at 24 months, pooled results showed the BMD increase difference between treatments was 1.74% at the spine, 1.22% at the total hip and 1.19% at the femoral neck, according to the researchers.
When looking at fracture risk, researchers did not observe a difference between denosumab and bisphosphonate treatments for reducing the risk for any type of fracture in pooled estimates at 12 months (RR = 1.32; 95% CI, 0.93-1.87) or at 24 months (RR = 0.81; 95% CI, 0.47-1.41), or for osteoporotic fractures specifically (RR = 0.92; 95% CI, 0.39-2.15) at 12 months. Only one study demonstrated denosumab had a lower osteoporotic fracture incidence than alendronate at 24 months (RR = 0.51; 95% CI, 0.27-0.97). Safety profiles were similar between treatments.
The researchers noted that several knowledge gaps remain regarding the comparative effectiveness of denosumab and bisphosphonate therapies. Evidence on the long-term BMD benefit with denosumab vs. bisphosphonate therapy is limited, they wrote, and only one study in the analysis reported the efficacy difference on fracture endpoint between denosumab and bisphosphonates at 2 years. Future longitudinal studies with longer follow-up and larger samples size are needed to examine differences in fracture endpoints, Lyu said.
“In clinical practice, the most commonly used anti-osteoporosis medications are bisphosphonates,” Lyu said. “When the first bisphosphonate is ineffective (eg, due to unsatisfactory response or fractures), a different medication should be considered. Results of this study suggest that in patients treated with a prior bisphosphonate, switching to denosumab would result in a greater increase of BMD than a switch to another bisphosphonate.” – by Regina Schaffer
For more information:
Houchen Lyu, MD, PhD, can be reached at Brigham and Women’s Hospital, division of rheumatology, immunology and allergy, 60 Fenwood Rd., Suite 6016, 6th Floor, Boston, MA 02115; email: houchen_lyu@hms.harvard.edu.
Disclosures: Lyu reports no relevant financial disclosures Please see the study for all other authors’ relevant financial disclosures.
Perspective
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This meta-analysis is suggestive, but not conclusive. The evidence is pretty clear that the long-term BMD gains with denosumab are much better than with bisphosphonates. It is not known how important that is. Based on 3-year data, BMD gains at the spine do not strongly correlate with fracture risk reductions. The correlation is stronger for BMD gains at the hip and hip fracture risk reduction, but not strongly.
In this meta-analysis, “bisphosphonates” appear to be lumped together when, in fact, they are different. The evidence for fracture reduction is not as strong for ibandronate as it is for the others.
Looking at the most recent 3-year placebo-controlled trials of zoledronic acid and denosumab, reduction in vertebral fracture risk (70% and 68%), hip fracture risk (41% and 40%) and non-vertebral fracture risk (25% and 20%), there really is no difference. Since longer-duration trials lack a placebo control group, no conclusions can be drawn about comparative fracture risk reduction beyond 3 years.
I tend to look at fracture risk categorically. Of medications intended for long-term use, four — alendronate, risedronate, zoledronic acid and denosumab — have been shown to have what I call “broad spectrum” anti-fracture efficacy, that is, vertebral, hip and nonvertebral fracture risk reduction. I do consider the greater BMD gains with denosumab in selecting among these choices. If the patient’s BMD is quite low, I tend to go with denosumab. If BMD is not so bad and would be OK just preventing loss, any of the agents would be OK. Non-oral agents are preferred for patients who might not tolerate or might not absorb oral drugs and for patients who cannot remember to take oral drugs.
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